2-(bis(p-substituted phenyl)methylene)adamantanes

ABSTRACT

2-(BIS(P-SUBSTITUTED PHENYL)METHYLENE)ADAMANTANES OF THE FORMULA   2-((4-(R1-O-)PHENYL)(4-(R2-O-)PHENYL)C=)ADAMANTANE   WHEREIN R1 AND R2 ARE THE SAME OR DIFFERENT AND ARE HYDROGEN, ALKYL OF FROM 1 THROUGH 5 CARBON ATOMS, CYCLOPENTYL.   -CO-R3   WHEREIN R3 IS HYDROGEN OR ALKYL OF FROM 1 THROUGH 10 CARBON ATOMS,   -(CH2)N-N(-R4)(-R5)   WHEREIN N IS 2 OR 3, AND R4 AND R5 ARE THE SAME OR DIFFERENT AND ARE HYDROGEN OR ALKYL OF FROM 1 THROUGH 4 ATOMS OR R4 AND R5 TAKEN TOGETHER WITH SAID NITROGEN ATOM FORM PIPERIDINO, PYRROLIDINO OR MORPHOLINO; AND PHARMACEUTICALLY ACCEPTABLE SALTS SAID COMPOUNDS WHEREIN AT LEAST ONE OF R1 AND R2 IS   -(CH2)N-N(-R4)(-R5)   ARE USEFUL FOR PREVENTING PREGNACY OF FEMAL WARMBLOODED ANIMALS.

"United States Patent O 3,711,556 2-[BIS(p-SUBSTHTUTED PHENYDMETHYLENE] ADAMANTANES Kyu Tai Lee, Wilmington, DeL, assignor to E. 1. du Pont de Nemours and Company, Wilmington, Del.

No Drawing. Filed June 13, 1968, Ser. No. 736,600 Int. Cl. C07c 39/16 US. Cl. 260-613 R 4 Claims ABSTRACT OF THE DISCLOSURE 2-[bis(p-substituted phenyl)methylene]adamantanes of the formula wherein R and R are the same or different and are hydrogen, alkyl of from 1 through 5 carbon atoms, cyclopentyl,

&R3 wherein R is hydrogen or alkyl of from 1 through 10 carbon atoms,

R4 (CH2)nN wherein n is 2 or 3, and R and R are the same or different and are hydrogen or alkyl of from 1 through 3 carbon atoms or R and R taken together with said nitrogen atom form piperidino, pyrrolidino or morpholino; and pharmaceutically acceptable salts of said compounds wherein at least one of R and R is are useful for preventing pregnancy of female warmblooded animals.

BACKGROUND OF THE INVENTION This invention relates to 2-[bis(p-substituted phenyl) methylene1adamantanes. It has been discovered that the subject compounds surprisingly are effective for preventing pregnancy of female warm-blooded animals.

This activity for the subject compounds is all the more startling when these compounds are compared in structure to contraceptive agents presently known to the medical art.

There are, at present, antifertility agents known to the medical arts. The agents which are known to be most effective for preventing pregnancy are estrogens and progestins.

Presently, the most widely accepted, orally effective, antifertility agents are mixtures of steroidal estrogens and progestins. When these agents are administered, a pseudopregnancy is established and ovulation is prevented. In order to induce this pseudopregnant condition, these agents are administered orally for about twenty days of the menstrual cycle. Although they are quite effective, this dosage regimen can result in side effects. The most commonly occurring side effects are similar to the ymptoms observed during pregnancy. These side effects include "Ice nausea, occasional vomiting, dizziness, headache, breast enlargement and pigmentation of the nipples, particularly during the first cycle in which these agents are administered.

The fact that these agents require a cyclic administration regimen also presents a problem. They must be administered without fail each day of the 20-day period or there is danger of breakthrough bleeding.

Whereas the estrogen-progestin mixtures now most widely used for the prevention of pregnancy must be taken for relatively long periods in anticipation of coitus in regular cycles, the compounds of this invention can be administered after coitus to prevent pregnancy. Furthermore, a cyclic regimen of administration is not required with the compounds of this invention. Although the exact mechanism of action is not well understood, animal tests indicate that nidation is in some manner prevented.

Therefore, in addition to the striking structural difference of the compounds of this invention over known contraceptive agents, it also appears that the compounds of this invention exhibit a mechanism of action that materially differs from presently employed contraceptive drugs.

This new mechanism of action has numerous practical advantages such as ease of use, elimination of protracted periods of administration, elimination of a scheduled regimen of medication, and the avoidance of a continual state of pseudopregnancy, which is responsible for many side effects.

SUMMARY OF THE INVENTION In summary, this invention relates to 2-[bis(p-substituted phenyl)methylene] adamantanes of the formula wherein R and R are the same or different and are hydrogen, alkyl of from 1 through 5 carbon atoms, cyclopentyl,

wherein R is hydrogen or alkyl of from 1 through 10 carbon atoms,

/R4 (OHz)nN wherein n is 2 or 3 and R and R are the same or different and are hydrogen or alkyl of from 1 through 3 carbon atoms or R and R taken together with said nitrogen atom form piperidino, pyrrolidino or morpholino; and pharmaceutically acceptable salts of said compound wherein at least one of R and R is /R4 -(CHz)nN The preferred compounds of Formula I are those wherein R and R are the same or different and are hydrogen, methyl, cyclopentyl, acetyl, propionyl or 2- pyrrolidinoethyl. The most preferred compounds of Formula I are the following:

2- [bis(p-hydroxyphenyl methylene] adamantane 2- [bis (p-methoxyphenyl methylene] adamantane 2- [bis (p-cyclopentyloxyphenyl )methylene] adamantane 2- [bis (p-a cetoxyphenyl) methylene] ad am antane 2- [bis (p-propionyloxyphenyl) methylene] adamantane 2-{ bis [p- Z-pyrrolidinoethoxy) phenyl methylene} adamantane Z-{bis [p- 2-pyrrolidinoethoxy) phenyl] methylene} adamantane dihydrochloride This invention is also directed to a method of preventing pregnancy of a female warm-blooded animal comprising administering to said animal an effective amount of a compound of Formula I.

This invention is further directed to a pharmaceutical composition effective for preventing pregnancy of a female warm-blooded animal when administered to said animal, said composition comprising a pharmaceutically acceptable diluent and an effective amount of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION A convenient starting material for the compounds of this invention is adamantane-Z-carboxylic acid [Landa et al., Z. Chem., 7, 388 (1967)] which can be prepared by reacting 2-hydroxyadamantane [P. von R. Schleyer and R. D. Nicholas, J. Am. Chem. Soc., 83, 183 (1961)] with a mixture of formic acid and sulfuric acid according to Koch reaction. Adamantane-2-carboxylic acid can be also prepared by oxidizing adamantane-Z-carboxaldehyde with silver oxide.

Compounds of Formula I wherein R and R are the same and are hydrogen, alkyls or (CHZ)..N

are prepared by reacting a tetrahydrofuran (THF) solution of adamantane-Z-carboxylic acid chloride, prepared by reacting thionyl chloride with the carboxylic acid, with two equivalent amounts of a Grignard reagent of the formula R MgBr wherein R (=R are alkyl or in THF. The resulting intermediate is treated with thionyl chloride in pyridine to give the desired product. The Grignard reagent used to prepare 2-[bis(p-hydroxyphenyl) methyl]adamantane, for example, is p-(Z-tetrahydropyranyloxy)phenyl magnesium bromide [Lednier et al., J. Med. Chenr, 9, 172 (1966)]. This resulting intermediate is reacted with thionyl chloride in pyridine, followed by treatment with alcoholic hydrochloric acid to give the desired product.

Compounds of Formula I wherein R and R are the same and are R4 H2)!.N

s can also be prepared by treating Z-[bis (p-hydroxyphenyl) methylene1adamantane with two equivalent amounts of appropriate amino alkyl chloride in the presence of two equivalent amounts of sodium methoxide in dimethylforrnamide (DMF). For example, reaction of one mole of 2-[bis(p-hydroxyphenyl)methylene]adamantane with two moles of 2-pyrrolidinoethyl chloride and two moles of sodium methoxide in DMF gives 2-{bis [p-(Z-pyrrolidinoethoxy)phenyl] methylene}- adamantane.

Compounds of Formula I wherein R and R are the same and are 0 JLR.

(acyl), are prepared by reacting 2- [bis (p-hydroxyphenyl) methyleneJadamantane with two equivalent amounts of acyl halide or acyl anhydride. For example, reaction of one mole of 2-[bis(p-hydroxyphenyl)methylene]adamantane with two moles of acetyl chloride in DMF in the presence of pyridine gives 2-[bis(p-acetoxyphenyl) methylene1adamantane. In order to prepare 2[bis(pformyloxyphenyl)methylene]adamantane, 2 [bis(p-hydroxyphenyl)methylene1adamantane is heated in formic acid in the presence of two equivalent amounts of acetic anhydride.

To prepare compounds of Formula I wherein R and R are different and are hydrogen, alkyl, or

the THF solution of adamantane-Z-carboxylic acid chloride is reacted with one equivalent amount of suitable Grignard reagent at 10() C., and the resulting 2- adamantyl-p-substituted phenyl ketone is isolated and then further reacted with a different Grignard reagent. The resulting alcohol is treated with thionyl chloride in pyridine to give the desired product. When one of the Grignard reagents used above is p-(Z-tetrahydropyranyloxy) phenyl magnesium bromide, the resulting alcohol is treated with thionyl chloride in pyridine, followed by alcoholic hydrochloric acid in order to prepare p-hydroxy derivatives. For example, reaction between one mole of ad-amantyl-2-carboxylic acid chloride and one mole of p-methoxyphenyl magnesium bromide at 10 -0 C. gives Z-aclamantyl p-methoxyphenyl ketone. This ketone is then reacted with one mole of p-(Z-tetrahydropyranyloxy)- phenyl magnesium bromide. The resulting alcohol is treated with thionyl chloride in pyridine, followed by alcoholic hydrochloric acid to give 2(p-methoxy-p-hydroxydiphenylmethylene -adamantane.

Compounds of Formula I wherein R and R are different and are (acyl), are prepared in following reaction sequence. One mole of adamantane-Z-carboxylic acid chloride is reacted with one mole of p-(Z-tetrahydropyranyloxy)phenyl magnesium bromide at -100 C. The intermediate is treated with alcoholic hydrochloric acid to give 2- adamantyl p-hydroxyphenyl ketone, which is acylated by means of the method described above. The resulting 2- adamantyl p-acyloxyphenyl ketone is reacted with one equivalent amount of p-(Z-tetrahydropyranyloxy)phenyl magnesium bromide. The intermediate alcohol is treated with thionyl chloride in pyridine, followed by alcoholic hydrochloric acid to give 2-(p-acyloxy-p-hydroxydiphenylmethylene)adamantane, which is then acylated as described above to give the desired product.

This invention will be better understood by reference to the following illustrative examples.

Example 1 A solution of 11 parts of Z-adamantane carboxyaldehyde in ml. of diethyl ether is added slowly into a mixture of 8 parts of sodium hydroxide, 200 ml. of water, 200 ml. of ethanol and 17 parts of silver oxide. The mixture is heated under reflux for four hours. The cooled mixture is diluted with SOO-ml. of water and filtered. The filtrate is concentrated under reduced pressure to approximately 500 ml. The aqueous solution is refiltered and acidified with 6 N hydrochloric acid. The solid precipitate is collected by filtration and dried to give Z-adamantane carboxylic acid.

Example 2 A mixture of 3.1 parts of Z-adamantane carboxylic acid and 30 parts of thionyl chloride is heated under reflux for 30 minutes. The excess thionyl chloride is removed by evaporation under reduced pressure to give Z-adamantane carboxylic acid chloride.

The anhydrous THF (25 ml.) solution of above acid chloride is added slowly into p-(Z-tetrahydropyranyloxy) phenyl magnesium bromide, prepared from 13 parts of p- (2-tetrahydropyranyloxy)phenyl bromide and 1.23 parts of magnesium turnings in 30 ml. of anhydrous THF by conventional method. The temperature is maintained at 20-25 C. during the addition. The mixture is stirred at room temperature for 15 hours and at 60 C. for 3 hours. The cooled mixture is poured into 50 ml. of saturated aqueous ammonium chloride solution. The organic layer is separated, dried over anhydrous magnesium sulfate, and concentrated to give an oily product.

The above product is dissolved in 50 ml. of pyridine and 5 ml. of thionyl chloride added slowly. The resulting mixture is stirred at room temperature for 3 hours and diluted with 300 ml. of water. The aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated to give an oily product.

The above product is dissolved in 50 ml. of ethanol and ml. of concentrated hydrochloric acid added slowly. After stirring at room temperature for one hour, the solid precipitate is collected by filtration. The solid is recrystallized from acetonitrile to give pure 2-[bis(p-hydroxyphenyl)methylene]adamantane; M.P. 256-2575".

Analysis.--Calcd. for C I-1 0 (percent): C, 83.09; H, 7.28. Found (percent): C, 83.04; H, 7.61.

Examples 3-7 The process of Example 2 is repeated substituting an equivalent amount of indicated Grignard reagent for p-.(Z-tetrahydropyranyloxy)phenyl magnesium bromide of Example 2 to obtain the indicated products.

A mixture of 0.32 part of 2-[bis(p-hydroxyphenyl) methylene]adamantane, 0.66 part of pyridine, 15 ml. of acetyl chloride and 10 ml. of dimethylformamide is heated on steam bath for two hours. The resulting solution is diluted with 100 ml. of water. The aqueous mixture is extracted with chloroform. The chloroform extract is washed with dilute sodium bicarbonate solution, water, dried over anhydrous magnesium sulfate, filtered and concentrated to give an oily product, which solidified on addition of 80% ethanol. The solid is collected by filtration and recrystallized from ethanol to give pure 2-[bis (p-acetoxyphenyl)methylene]adamantane; M.P. 163.5- 165.5

Analysis.Calcd. for C H O (percent): C, 77.86; H, 6.78. Found (percent): C, 77.74; H, 6.49.

Examples 9 and 10 The process of Example 8 is repeated substituting an equivalent amount of indicated acid chloride for acetyl chloride of Example 8 to obtain the indicated products.

Acid chloride Product Example:

9 Propionyl chloride 2-[bis(p-propionyloxyphenyD-methylene] adamantane.

10 n-Valeryl chloride 2-[bis(p-n-va1eryioxyphenyD-methylene] adamantane.

Example 11 A mixture of 0.1 mole of Z-[bis-(p-hydroxyphenyl)- methylene]adamantane and 0.2 mole of acetic anhydride in ml. of 98% formic acid is heated under reflux for 5 hours. On evaporation, there is obtained 2-[bis (p-formyloxyphenyl)-methylene] adamantane.

Example 12 To a mixture of 0.5 mole of 2-[bis(p-hydroxyphenyl)- methylene]adamantane and 1 mole of sodium methoxide in 200 ml. of dimethylformamide is added 1.2 mole of 2- pyrrolidinoethyl chloride. The resulting mixture is stirred at 4050 for 4 hours and diluted with 500 ml. of water. The organic product is extracted with chloroform and the chloroform extract is washed with water, dried over magnesium sulfate and concentrated to give 2-{bis[p-(2- pyrrolidinoethoxy)phenyl]methylene}adamantane.

Examples 13 and 14 The process of Example 12 is repeated substituting an equivalent amount of indicated aminoalkyl chloride for 2-pyrrolidinoethyl chloride of Example 12 to obtain the indicated products.

Aminoalkyl chloride Product Example:

13 2-N,N-dimethylaminoethyl 2-(biS[D-(2-N,N-dimethyichloride. aminoethoxy)phenyl]- methylene ladamantane. 14 3-morpholinopropyl chloride 2-lbiS[p-(3-morpholinopropyloxy)phenyl]- methylene ladamantane.

Example 15 To a solution of 0.5 mole of Z-adamantane carboxylic acid chloride in 100 ml. of anhydrous THF is added 0.5 mole of p-methoxyphenyl magnesium bromide in 100 ml. of anhydrous THF at 10. The resulting mixture is stirred at 10 for one hour and poured into 200 ml. of saturated ammonium chloride solution. The organic layer is separated and dried over anhydrous magnesium sulfate and concentrated to give 2-adamanty1 p-methoxyphenyl ketone.

Examples 16 and 17 The process of Example 15 is repeated substituting an equivalent amount of indicated Grignard reagent for pmethoxyphenyl magnesium bromide of Example 15 to obtain the indicated ketone.

Grignard reagent Ketone Example:

16 p-Cyclopentyloxyphenyl Z-adamantyl p-cycl0pentylmagnesium bromide. oxyphenyl ketone.

17 p-Pyrrolidinoethoxyphenyl Z-adamantyl p-(2-pkrrolimagnesium bromide. dinoethoxy) phenyl ketone.

Example 18 7 8 ing mixture is stirred at room temperature for 3 hours steam bath for one hour. The resulting solution is diluted and diluted with 600 ml. of water. The aqueous mixture with 200 ml. of chloroform and washed with cold 5% is extracted with chloroform. The chloroform solution is potassium carbonate solution and water. The chloroform washed with water, dried over anhydrous magnesium sulsolution is dried over anhydrous magnesium sulfate and fate, and concentrated to give Z-adamantyl p-hydroxy- 5 concentrated to give 2-[p-acetoXy-p-(2-pyrrolidinoethoxy) phenyl ketone. diphenylmethylene]adamantane.

This ketone is reacted with various acyl chlorides as in Example 8 to give the following products: Examples 27-30 Acyl chloride: Produ t The process of Example 26 is repeated substituting an Acetyl chloride Z-adamantyl p- 10 equivalent amount of indicated hydroxy compound for acetoxyphenyl ketone. 2 [p-hydroxy-p'-(2 pyrrolidinoethoxy)diphenylmethyl- Propionyl chloride Z-adamantyl pene]adamantane and acid chloride for acetyl chloride propionyloxyphenyl ketone. of Example 26 to obtain the indicated product.

Hydroxy compound Acid chloride Product Example: I

27 2-(p-methoxy-p-hydroxydipheny1meth- Acetyl chloride Z-(p-acetyoxy-p-methoxydlphenylmethylene)adamantane. ylene)adamantane. 28 2-(p-cyclopentyloxy-p-hydroxydiphenyl- ..do 2-(pacetoxy-p-cyc10pentyloxyd1phenylmethylene) adamantane. methylene) adamantane. I 29 2-(phydr0Xy-p-n1orpholin0ethoxydiphenyl- Propionylchloride Z-[o-(Zmorphohnoethoxy)-p-prop1onyloxymethylene)adamantane. drphenylmethylene]adamantane. 30 2-(p-acctoxy-p-hydroxydipheny1methyldo 2-(p-acet0xy-p-propionyloxydiphenyl ene)adamantane. methylene)adamantane.

Example 19 Examples 31-33 To a Solution of mole of z-adamafltyl p' f The salts of aminoalkyl ethers are prepared by adding P y ketone 111 100 1111- Of anhydrous THF 15 added equivalent amounts of organic acids or excess of anhy- 05 mole of P4 ttitlrahydFOPYFQIIYIQXY)phfinyl magnedrous hydrogen chloride into a solution of desired amino- Sium bromide in 100 of anhydf 011$ The mixture alkyl ethers in anhydrous tetrahydrofuran. The precipitate is stirred at room temperature for 10 hours and then at i ll d by filtration. By using the process, th f l- 50 for 2 hours. It is poured into 200 ml. of saturated lowing Salts are prepared aqueous ammonium chloride solution. The organic layer is separated, dried over anhydrous magnesium sulfate, and Example: Product concentrated to give an oily product. 31 Z-{bis [p-(Z-pyrrolidinoethoxy)phenyl]- The above oily product is dissolved in 200 ml. of pyrimethylene}adamantane dihydrochloride. dine and 0.5 mole of thionyl chloride added. The mixture 32 2-{bis[p-(2-N,N-dimethylaminoethoxy)- is stirred at room temperature for 4 hours and diluted phenyl]methylene}adamantane dimaleate. with 1 liter of water. The aqueous mixture is extracted 33 2-[p-acetoxy-p'-(2-pyrrolidinoethoxy)-diwith chloroform and the chloroform extract is washed phenylmethylene]adamantane succinate. with water, dried over anhydrous magnesium sulfate and conoomratod to i an il d The compounds of Formula I can be administered to The above oil is dissolved in 300 ml. of ethanol and Prevent pregnancy in Warm-blooded animals according to 30 1 f Concentrated hydrochloric acid added The the method of this invention by any suitable means. Oral l i mixture i i d at room temperature f one administration is preferred. Administration also can be hour. The solid precipitate is collected by filtration to give Parentfiral, that is Subcutaneous intramuscular, 2-( h d i h l h l rectal. Compounds of this invention are preferably administered in a single dose, preferably orally, after coitus Examples 20-25 but before implantation of the fertilized egg. Alternatively, single or divided doses can be administered daily The process of Example 19 is repeated substituting an during all or a substantial fraction of the estrous cycle equivalent amount of indicated ketone for Z-adamantyl or menstrual cycle. panethoxyphenyl ketone of Example 19 and Grignard Doses will ordinarily range from about 0.0005 to about reagent for p-(2 tetrahydropyranyloxy)phenyl magne- 50 milligrams per kilogram of body weight of the resium bromide of Example 19 to obtain the indicated cipient per day (mg./kg.-day). The preferred dosage product. range is from about 0.0025 to about 10 mg./kg.-day, and

Ketone Grignard reagent Product Example:

20 2-adamanty1p-methoxyphenylkctonc p-Cyclopentyloxyphenyl magnesium bro- 2-(p-methoxy-p-eyclopentyloxydiphenyl mide. methylene)adamantane. 21 do p-pyrrolidinoethoxyphenyl magnesium bro- 2-[p-methoxy-p-(Z-pyrrolidinoethoxy)dibromide. phenylmethylene]adamantane. 22 Z-adamantyl p-eyelopentyloxyphenyl kep-(Z-tetrahydropyranyloxy)phenyl magne- 2-(p-cyclopentyloxy-p-hydroxydiphenyltone. I sium bromide. methylene)adamantane. 23 Z-adamantyl p-pyrrohdmoethoxyphenyl ke- .do.. 2-[p-hydroxy-p-(2-pyrrolidinoethoxy)ditone. phenylmethylene]adamantane. 24 2adamantyl p-acetoxyphenyl ketone d0 2-( gacet0ziy-p-hydroxydiphenylmethylene)- a aman ane. 25 Zedamantyl p-propionyloxyphenyl ketone .d0 2-(p-hydroxy-p-propionyloxydiphenylmethylene)adamantane.

Example 26 the most preferred range is from about 0.005 to about 5 mg./kg.day.

A mixture of 0.1 mole of 2-(p-hydroxy-p'-pyrrolidino- EMMPLE 34 ethoxydiphenylmethylene)adamantane, 50 ml. of acetyl Immature female rats (28 days old) are induced into Qhloride, and 100 ml. of dimethylformarnide is heated on precocious puberty with a single dose of pregnant mares serum gonadotrophin and then are mated with normal males. 2 [bis(p-hydroxyphenyl)methylene]adamantane suspended in sesame oil is orally administered in graded doses to numerically equal groups of these female rats for six days starting on the day of finding sperm or a vaginal plug. One week after mating, the animals are killed and their uteri are examined for implantation sites. If any are found, the animal is considered pregnant. Control animals have a mean of eight implantation sites. The dose level at which fifty percent of the animals show no evidence of pregnancy, the ED is between 0.078 and 0.31 mg./kg.-day.

EXAMPLE 35 Example 34 is repeated substituting 2-[bis(p-acetoxy phenyl)methylene]adamantane for the 2-[bis(p-hydroxyphenyl)-methylene]adamantane. The ED of 2-[bis(pacetoxyphenyl)methylene]adamantane is between 0.078 and 0.31 mg./kg.-day.

The compounds of this invention can also be employed with equally satisfactory results to prevent pregnancy in other laboratory animals such as guinea pigs, rabbits, monkeys and chimpanzees and are also effective in preventing pregnancy in domestic animals such as swine, cows, sheep and horses. In small animals it is usually convenient to administer the compounds of this invention in the form of a capsule, or incorporated in the feed of the animal. However, when these compounds are administered to large animals, it is often more convenient to adminster them parenterally.

The compounds of Formula I can be employed in useful compositions according to the present invention in such dosage forms as tablets, capsules, powder packets, or liquid solutions, suspensions, or elixirs, for oral administration or liquid solutions for parenteral use, and in certain cases, suspensions for parenteral use. In such compositions, the active ingredient will ordinaril always be present in the amount of at least 0.01% by weight based on the total weight of the composition and not more than 90% by weight.

Besides the active ingredient of this invention, the composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, the solid carrier is a capsule which can be of the ordinary gelatin type. The capsule will contain from about 01-75% by weight of a compound of Formula I and 99.925% of a carrier.

In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets and employed. These capsules, tablets, and powders will generally constitute from about 0.5% to about 95% and preferably from 1% to 50% by weight of active ingredient. These dosage forms preferably contain from about 0.5 to about 250 milligrams of active ingredient, with from about 1 milligram to about 50 milligrams most preferred.

The pharmaceutical carrier can, as previously indicated, be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, and the like. In general water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injectable solutions. Sterile injectable solutions such as saline will ordinarily contain from about 0.05% to 25%, and preferably about 0.1% to 5% by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspension, syrup or elixir in which the active ingredient ordinarily will constitute from about 0.01 to 5% and preferably about 0.05 to 1% by weight. The pharmaceutical carrier in such composition can be an aqueous vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.

10 Suitable pharmaceutical carriers are described in Remingtons Pharmaceutical Sciences by E. W. Martin, a well-known reference text in this field.

In addition to the exemplary illustrations above, the following examples further explain one aspect of the present invention.

'EXAMPLE 3 6 G ./l0,0 00 Hard gelatin capsule, ingredients MgJcapsule capsules 2-[bis( -methox hen 1) meth lene adan iantanmi luz 10. 0 Magnesium stearate, U SP 3. 5 35 Tale, USP. 14. 0 Anhydrous lactose, USP 147. 5 1, 475

Finely divided 2-[bis(p-methoxyphenyl)methylene]- adamantane is intimately mixed with the magnesium stearate, talc and anhydrous lactose which have been previously screened to 50 mesh. The powder is used to fill #3 hard gelatin capsules using standard capsule filling equipment.

EXAMPLE 37 Soft gelatin capsule.-A solution of 1 part by weight of 2-[bis(p-acetoxyphenyl)methylene]adamantane in 225 parts by weight of soybean oil is prepared by warming the two components to 50 C. The solution is cooled and pumped into gelatin to form capsules using standard equipment. Each capsule contains 1.0 mg. of the active ingredient.

The active ingredients, lactose, microcrystalline cellulose, magnesium stearate and Cab-o-Sil are screened to 50 mesh. The ingredients are mixed to form a uniform powder and compressed into tablets weighing 100 mg.

EXAMPLE 39 Injection.-A solution is prepared consisting of: 1 part of 2-{bis [p- Z-pyrrolidihoethoxy) phenyl] methylene}-adamantane, hydrochloride and 18 parts of sodium chloride, USP in enough Water for Injection, USP to make 2 liters. Glass ampuls (1 m1.) are filled with the solution, sealed and autoclaved until the contents are sterile.

In other tablet formulations from one to seven percent of the total weight of the dosage form can be comprised of a lubricant or glidant such as talc, stearic acid, calcium stearate and the like in place of the magnesium stearate of the above formulations. Binders such as starch, ethylcellulose, polyethyleneglycol 4,000, gelatin and the like can be added to the above formulations with satisfactory results. Other fillers which can be substituted for the lactose of the above formulation include calcium sulfate, calcium phosphate, starch, manitol and the like.

A large variety of compositions according to this invention can thus readily be made by substituting other compounds for this invention, and including specifically, but not limited to, compounds for this invention that have specifically been named hereinbefore. The compounds will be used in the amounts indicated in accordance with procedures well known and described in the Martin text mentioned above.

Since many different embodiments of the invention can be made Without departing from the spirit and scope thereof, it is to be understood that the invention is not lim- 1 1 l 2 ited by the specific illustrations except to the extent de- References Cited fined in the following claims- I claim: 1. A compound which is represented by the formula 3,298,998 1/1967 McConnell et 260 619 X A 5 3,361,717 1/1968 Gilbert 260619 X A 3,663,602 /1972 Steinman 260613 R X 3,287,397 11/1966 Olsson et al. 260-619 A X Q OR OTHER REFERENCES 2 Stetter et al.: Chem. Abstracts, vol. 4, p. 4957g (1966) wherein HOWARD T. MARS, Primary Examiner R and R are the same or diiferent and are hydrogen, N M TE t alkyl of from 1 through 5 carbon atoms or cyclo- 15 ORGENS Assls ant Exammer 2 P13121511 h 1 h 1 1111 1 d t 1s py roxyp eny rne yene a aman ane.

th h 1 th 1 d t 260247, 247.7 A, 247.7 B, 247.7 G, 293.56, 293.58, me oxyp enyme yeneJa man we 293.59, 293.61, 326.81, 479 R, 501.1, 570.7, 619 A;

4.2-bis 1 DtlO h 16th] d tame. (D We ope y Xyp enyhn yenfla man 20 424248, 263, 274, 299, 325, 341, 346, DIGEST 14 Notice of Adverse Decisitm in Interference In Interference No. 98,594, involving Patent No. 3,711,556, K. T. Lee, 2- [BIS (P-SUBSTITUTED PHENYL) METHYLENE]ADAMANTANES, final judgment adverse to the patentee was rendered Apr. 1, 1975, as to claims 1, 2 and 3.

[Ofiicial Gazette August 5,1975.] 

